miRNAs and High-Density Lipoprotein metabolism

Abstract

Altered lipoprotein metabolism plays a key role during atherogenesis. For over 50years, epidemiological data have fueled the proposal that HDL-cholesterol (HDL-c) in circulation is inversely correlated to cardiovascular risk. However, the atheroprotective role of HDL is currently the focus of much debate and remains an active field of research. The emerging picture from research in the past decade suggests that HDL function, rather than HDL-c content, is important in disease. Recent developments demonstrate that miRNAs play an important role in fine-tuning the expression of key genes involved in HDL biogenesis, lipidation, and clearance, as well as in determining the amounts of HDL-c in circulation. Thus, it has been proposed that miRNAs that affect HDL metabolism might be exploited therapeutically in patients. Whether HDL-based therapies, alone or in combination with LDL-based treatments (e.g. statins), provide superior outcomes in patients has been recently questioned by human genetics studies and clinical trials. The switch in focus from "HDL-cholesterol" to "HDL function" opens a new paradigm to understand the physiology and therapeutic potential of HDL, and to find novel modulators of cardiovascular risk. In this review we summarize the current knowledge on the regulation of HDL metabolism and function by miRNAs. This article is part of a Special Issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernández-Hernando and Yajaira Suárez.

Keywords: Atherosclerosis; Cardiovascular disease; Cholesterol; HDL; Lipoproteins; miRNA.

Fig. 1. Mobilization of cholesterol via HDL particles

The lipidation of lipid-poor APOA1 in the hepatocyte (and in minor proportion in the enterocyte and adipocyte) generates pre-β HDL, which is further lipidated in the peripheral vasculature via ABCA1 and possibly ABCG1. Unesterified cholesterol in the nascent particle is esterified by LCAT. HDL exchanges lipids and apolipoproteins with APOB-containing lipoproteins (not shown in the figure). Clearance of HDL-bound cholesteryl esters is facilitated by SR-B1 in the liver. Excess hepatic cholesterol is eventually metabolized to bile acids and excreted through bile. miRNAs known to target transcripts involved in HDL biogenesis and the reverse cholesterol transport pathway are annotated in red boxes.